Since the mid-1960's alterations of amine neurotransmitter systems (norepinephrine (NE), serotonin (5HT) and dopamine (DA)) have been indirectly implicated in the pathophysiology of the major mental illnesses, depression and schizophrenia. Although direct demonstrations of abnormalities have not been consistently possible except for the separation of unipolar and bipolar depression on the basis of the NE metabolite MHPG in urine, findings using newer techniques and strategies continue to implicate the amine neurotransmitters. We have continued to study cerebrospinal fluid (CSF), plasma and urine from drug-free patients with affective illness and schizophrenia using more sensitive and comprehensive characterization of the neurotransmitter systems. Careful control of sources of variance and selection of appropriate age- and sex-matched controls have resulted in several new lines of evidence consistent with neurotransmittor dysregulation in mental illness: 1. Although not clearly seen in previous studies, NE and MHPG in CSF are now found to be lower in bipolar than unipolar depression. 2. Unstimulated resting plasma NE and MHPG is either no different or lower than in appropriately matched volunteers (contradicting earlier reports), whereas stimulated values are proportionally higher. 3. Urinary MHPG alone can be a misleading marker; a more robust measure of NE turnover can now be provided through simultaneous measures of other important metabolites normetanephrine and VMA as well. 4. Indices of 5HT and DA function in the CSF are highly interindependent and related to those of NE under some conditions; schizophrenics with wide ventricles have lower concentrations of both 5HT and DA metabolites and respond poorly to treatment. Measures of the same systems in plasma are in a developmental change but preliminary results suggest that the DA metabolite, HVA, in plasma shows abnormal variance in schizophrenic patients.